Maintenance of an adequate supply of oxygen to the body tissues is vital to survival. In the United States alone, several million people suffer from anemia secondary to renal failure, chronic inflammatory disease and malignancies (U.S. Pat. No. 4,987,121, hereby incorporated by reference in its entirety). Since to a large degree the oxygen-carrying capacity of blood is governed by the concentration of erythrocytes in the blood, the appropriate regulation of erythropoiesis is also crucial.
The early studies of Reissmann (Reissmann, K. R., Blood 5:372–80 (1950)) and Erslev (Erslev, A., Blood 8:349–57 (1953)) clearly demonstrated the hypoxia-induced stimulation of erythropoietin secretion. When erythropoietin is secreted from the erythropoietin-producing cells in response to hypoxia, it travels through the blood to its target organ, the hematopoietic tissues. In humans, the principal hematopoietic tissue is within the liver before birth, and in the bone marrow after birth. (Id.) There, erythropoietin binds specifically to its receptor on the erythroid progenitor cells called burst forming unit-erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E) and stimulates these cells to proliferate and differentiate (Spivak, J. L., Int. J. Cell Cloning 4:139–66 (1986)). BFU-E are the earliest erythroid progenitors and constitute 0.01%, approximately, of the nucleated bone marrow cells. CFU-E are derived from BFU-E, account for about 0.1% of marrow cells, and are much more responsive to erythropoietin than are BFU-E (Spivak, J. L., supra); Sawada, K., et al., J. Clin. Invest. 80:357–66 (1987)).
The low erythropoietin levels always present appear sufficient for a basal erythropoiesis rate. Relatively small losses of blood do not appear to stimulate increased erythropoietin production (Kickler, T. S., et al., J. Am. Med. Assoc. 260:65–7 (1988)). It is only after a major blood loss that there is an increased production of erythropoietin and rate of erythropoiesis.
It has been well-established that the majority of patients with renal insufficiency and anemia have serum erythropoietin levels well below what would be expected for the degree of anemia (Caro, J., et al., J. Lab. Clin. Med. 93:449–58 (1979); Radtke, H. W., et al., Blood 54:877–84 (1979); Chandra, M., et al., J. Pediatr. 113:1015–21 (1988)), although they can still respond to hypoxia with an increase in serum erythropoietin levels (Radtke, H. W., et al., Blood 54:877–84 (1979); Chandra, M., et al., J Pediatr 113:1015–21 (1988)). However, this markedly blunted erythropoietin response substantially contributes to the pathogenesis of the anemia (Eschbach, J. W., et al., Am J Kid Dis 11:203–9 (1988)). As a result, patients suffering from chronic renal failure and end-stage renal disease, or those undergoing renal transplantation, develop severe anemia and require regular blood transfusions (Royet, U.S. Pat. No. 5,482,924).
The use of recombinant human erythropoietin has facilitated treatment of these patients. However, recombinant erythropoietin treatment is extremely costly, and methods that augment the effect of erythropoiesis will permit the use of smaller doses of erythropoietin, and thus will decrease treatment costs. Additionally, increasing the rate of erythropoiesis would significantly improve clinical benefits for the treatment of congenital or acquired aplastic or hypoplastic anemia associated with chronic renal failure, end-stage renal disease, renal transplantation, cancer, AIDS, chemotherapy, radiotherapy, bone marrow transplantation and chronic diseases.